Severe Growth Failure Research Articles

Novel XRCC4 Mutations in an Infant With Microcephalic Primordial Dwarfism, Dilated Cardiomyopathy, Subclinical Hypothyroidism, and Early Death: Expanding the Phenotype Of XRCC4 Mutations

Microcephalic primordial dwarfism (MPD) is a group of clinically and genetically heterogeneous disorders which result in severe prenatal and postnatal growth failure. X-ray repair cross-complementing protein 4 (XRCC4) is a causative gene for an autosomal recessive form of MPD. The objective of this report is to describe novel XRCC4 mutations in a female infant with MPD, dilated cardiomyopathy, and subclinical hypothyroidism. Genetic testing was performed using a comprehensive next generation sequencing panel for MPD, followed by targeted XRCC4 gene sequencing. We report the case of a 970-gram, 35-cm, female infant (weight z score -5.05, length z score -4.71) born at 36 weeks and 3 days gestation. Physical examination revealed triangular facies, micrognathism, clinodactyly, and second and third toe syndactyly. Initial echocardiogram at birth was normal. Follow-up echocardiogram at 60 days of life revealed dilated cardiomyopathy with moderate left ventricular systolic dysfunction (ejection fraction was 40 to 45%), and anticongestive therapy was initiated. Thyroid testing revealed subclinical hypothyroidism with elevated thyroid-stimulating hormone of 13.0 μIU/mL (reference range is 0.3 to 5.0 μIU/mL) and normal free thyroxine by dialysis of 1.6 ng/dL (reference range is 0.8 to 2.0 ng/dL). Levothyroxine was initiated. Postnatal growth remained poor (weight z score at 3 months -4.93, length z score at 3 months -6.48), including progressive microcephaly (head circumference z score at 3 months -10.94). Genetic testing revealed novel compound heterozygous XRCC4 variants in trans: c.628A>T and c.638+3A>G. The child ultimately had cardiopulmonary arrest and died at 6 months of life. Molecular diagnosis in MPD is key to defining the natural history, management, and prognosis for patients with these rare disorders.

A novel heterozygous STAT5B variant in a patient with short stature and partial growth hormone insensitivity (GHI)

BackgroundThe most frequent monogenic causes of growth hormone insensitivity (GHI) include defects in genes encoding the GH receptor itself (GHR), the signal transducer and activator of transcription (STAT5B), the insulin like-growth factor type I (IGF1) and the acid-labile subunit (IGFALS). GHI is characterized by a continuum of mild to severe post-natal growth failure. ObjectiveTo characterize the molecular defect in a patient with short stature and partial GHI. Patient and methodsThe boy was born at term adequate for gestational age from non-consanguineous normal-stature parents. At 2.2 years, he presented proportionate short stature (height −2.77 SDS), wide forehead and normal mental development. Whole-exome analysis and functional characterization (site-directed mutagenesis, dual luciferase reporter assay, immunofluorescence and western immunoblot) were performed. ResultsBiochemical and endocrinological evaluation revealed partial GH insensitivity with normal stimulated GH peak (7.8 ng/mL), undetectable IGF1 and low IGFBP3 levels. Two heterozygous variants in the GH-signaling pathway were found: a novel heterozygous STAT5B variant (c.1896G>T, p.K632N) and a hypomorphic IGFALS variant (c.1642C>T, p.R548W). Functional in vitro characterization demonstrated that p.K632N-STAT5b is an inactivating variant that impairs STAT5b activity through abolished phosphorylation. Remarkably, the patient's immunological evaluation displayed only a mild hypogammaglobulinemia, while a major characteristic of STAT5b deficient patients is severe immunodeficiency. ConclusionsWe reported a novel pathogenic inactivating STAT5b variant, which may be associated with partial GH insensitivity and can present without severe immunological complications in heterozygous state. Our results contribute to expand the spectrum of phenotypes associated to GHI.

P012 Successful Use of Combination Biologic Therapy in Medically Refractory Pediatric Crohn's Disease and Sacroiliitis

CASE: We present a patient with medically refractory Crohn’s disease, sacroiliitis and growth failure who showed remarkable response to combination therapy using two different biological agents along with an immunomodulator and no significant adverse events. A 14-year old male presented for 2nd opinion regarding management of refractory ileocolonic Crohn’s disease. He was diagnosed with Crohn’s disease at an outside center at 9 years of age. Initial treatment with systemic steroids and azathioprine was unsuccessful. He had sub-optimal clinical improvement on anti-tumor necrosis factor (TNF) therapy that included infliximab for 1 year, followed by adalimumab for 1.5 years. He subsequently struggled with repeated episodes of Clostridium difficile (CDI) requiring prolonged vancomycin taper. His therapy was then switched to vedolizumab, systemic steroids and azathioprine which provided some symptomatic relief, but he was noted to be persistently anemic with elevated inflammatory markers and poor growth. At the time of presentation to our center he was steroid dependent on prednisone 5 mg daily for 6 months while still on vedolizumab and azathioprine. He had mildly active clinical disease but severe growth failure and was negative for CDI. Repeat disease assessment noted severe granulomatous colitis and terminal ileitis with worsening disease in the distal colon. He was treated with Budesonide MMX and mesalamine enemas with no improvement. Vedolizumab levels were noted to be low and therefore therapy escalated to every 4-week intervals. Azathioprine was stopped due to lack of efficacy despite adequate levels. Due to body mass index (BMI) z-score of -2.4, exclusive enteral therapy was implemented for 3 months followed by transition to regular diet. His weight improved but there was no change in clinical activity or laboratory abnormalities. He subsequently developed leg and hip pain. Rheumatology evaluation was pursued, and he was diagnosed with sacroiliitis based on physical examination and a lumbosacral MRI. At this point a decision was made to use combination of two biologicals due to prior history of GI disease refractory to anti-TNF therapy. Adalimumab and oral methotrexate were given in addition to vedolizumab. He has been on this combination for last 9 months with no adverse events. Patient has shown excellent clinical response with normalization of inflammatory markers and resolution of anemia. His BMI z-score improved to 0.76 with weight gain of 25 kilograms in the past year. Combination biologicals are rarely utilized due to concerns for side effects and high cost making it difficult to obtain insurance approval. When used judiciously in patients with medically refractory disease it can be safe and effective. A paucity of literature exists regarding the use of combination biologicals especially in children.

A homozygous mutation in the highly conserved Tyr60 of the mature IGF1 peptide broadens the spectrum of IGF1 deficiency.

IGF deficiency caused by a homozygous loss-of-function of IGF1 is a very rare cause of growth failure. This paper comments on an original research paper in this issue on a novel patient with this condition, confirming its main clinical features (severe prenatal and postnatal growth failure, severe microcephaly, retrognathia, sensorineural deafness and severe global developmental delay) and adding information about the variability of the growth hormone secretion, IGF1 concentration and insulin sensitivity.

220.5: Diagnosis and management of congenital enteropathies: analysis of a large multi-center cohort and the role of Next Generation Sequencing.

Introduction: A small percentage of children with intestinal failure suffer from congenital enteropathies responsible for chronic diarrhea associated with severe growth failure and dehydration. These disorders usually present early in infancy and result from monogenic mutations in genes affecting intestinal epithelial function. Recently, next-generation sequencing (NGS) technology has revolutionized the approach to molecular diagnosis, although there still remains little information about the associated natural history, and complete clinical phenotype. To better understand the natural history and the impact of NGS, we studied a historical cohort of children with congenital enteropathies. Methods: A retrospective analysis of children followed in the intestinal failure / congenital enteropathy programs at Necker-Enfants Malades and Boston Children’s Hospitals was done. Diagnosis was obtained either from pathology, targeted sequencing, and from 2012 (Boston)/ 2014 (Paris) by NGS (whole exome, or targeted gene panels). Genetic findings were validated clinically and/or functionally. Results: 85 patients were included (53% female, age 2 months to 25 years). Three out 85 patients died. In 82% (70/85) of cases, a diagnosis could be established. 25 (29%) patients were diagnosed with microvillus inclusion disease (MYO5B mutation), 19 (22%) patients were diagnosed with tufting enteropathy (EPCAM mutations). Other diagnoses included DGAT1 mutations (8,5%), TTC37/SKIV2L, and SLC26A3 [UMO1] mutations. Since 2012, 37 out of 46 patients (80%) obtained a molecular diagnosis, including the discovery of novel genes (DGAT1, UNC45A, WNT2B). 9 out of 42 patients at Necker-Enfants Malades underwent intestinal transplantation. In a number of patients, diagnosis facilitated by NGS led to significant changes in clinical management such as removal of high-risk immunosuppressive medications. Conclusion: We carried out an analysis of a large cohort of children with congenital enteropathy, across two major pediatric centers. Mutations in MYO5B and EPCAM were responsible for 51% of our cohort, with considerable genetic heterogeneity in the rest of the cohort. Since 2012, most patients underwent NGS, with a molecular diagnosis achieved in 80% of cases[UMO2]. NGS was critical in achieving a diagnosis particularly in atypical or hypomorphic presentations and enabled clinically significant changes in management as well as the discovery of novel disease-causing genes.

Growth hormone deficiency in children with antenatal Bartter syndrome.

Background Bartter syndrome is a group of rare autosomal-recessive renal disorders characterized by hypokalemic hypochloremic metabolic alkalosis associated with severe growth failure; the exact causes for growth retardation are unclear. GH deficiency (GHD) has been reported in a few cases of Bartter syndrome. The aim of our study was to determine the prevalence of GHD in children with antenatal Bartter syndrome and to assess their response to GH therapy. Methods Ten patients aged 1.5-14.5 years and diagnosed with antenatal Bartter syndrome were enrolled. Seven children with short stature underwent GH stimulation tests. Results Common presenting symptoms were failure to thrive and polyuria. The mean patient height at study entry was -2.7 standard deviation (SD) (range 0.89 to -5.95) and mean weight (SD) was -1.7 (range 1.89 to -4.11). A decline in height and weight (SD) was observed over the years. GHD was diagnosed in four children and GH therapy was started in all of them. Two patients responded very well and gained >1 SD in height, one patient stopped therapy due to non-adherence and one had a poor response. Conclusions In addition to other important causes for poor growth in antenatal Bartter syndrome, our findings suggest that GHD should also be considered as a cause of growth retardation and therefore, clinical assessment of the GH axis is recommended. GH therapy has a role in the treatment of growth failure in some individuals with Bartter syndrome.

DNA Ligase IV Syndrome: A Rare Cause of Growth Failure & Hypogonadism

DNA ligase IV syndrome is a rare genetic disorder characterized by pronounced radiosensitivity, growth failure, pancytopenia, hypogonadism, and immunodeficiency. Here, we describe a unique case of DNA ligase IV syndrome diagnosed in adulthood and review the endocrine manifestations of this rare disorder. We present detailed clinical, laboratory, and exam findings and review the relevant literature. This patient initially presented in childhood with microcephaly, growth failure, and mild pancytopenia. At age 18, she developed secondary amenorrhea, with labs revealing hypergonadotropic hypogonadism. She was initially suspected to have Turner syndrome, but karyotype testing was normal. At age 34, genetic testing ultimately confirmed the diagnosis of DNA ligase IV syndrome. Severe growth failure and hypogonadism are important endocrine clues to the diagnosis of DNA ligase IV syndrome. The increased availability of genetic testing and whole-exome sequencing may allow for definitive diagnosis in patients that previously went unrecognized.

Novel mutation of type-1 insulin-like growth factor receptor (IGF-1R) gene in a severe short stature pedigree identified by targeted next-generation sequencing

Insulin-like growth factor receptor (IGF-1R) deficiency is a rare form of short stature, and is difficult to clinically diagnose. Targeted next-generation sequencing (NGS) allows for the rapid and inexpensive assessment of short stature. We identified mutations in the pedigree of a Chinese boy with severe short stature using targeted NGS; we then assessed the clinical characteristicsand evaluated the efficacy of growth hormone therapy. NGS analysis revealed a novel heterozygous missense mutation in exon3 (c.926C>T, p.S309L) of the type-I IGF-1R gene in the proband, which was inherited from the mother. The proband, mother and grandfather suffered from severe growth failure. After recombinant human growth hormone therapy, the patient's growth rate increased. The novel missensemutation in IGF-1R (c.926C > T, p.S309L) is associated with severe short stature in Chinese individuals. Targeted NGS may enable efficient diagnosis and genetic consultation of children with short stature.

THE UNBEARABLE LIGHTNESS OF PRESCRIBING GROWTH HORMONE

Short stature is the most visible and prominent physical characteristic and one of the commonest reason for referral to pediatric endocrinologist. It is assumed as disabling condition with psychosocial consequences that seeks treatment. Behind short stature severe pathology could be hidden, although not necessarily of endocrine origin. Even in the new millennium, many diagnostic pitfalls and dilemmas persist in confirmation of growth hormone deficiency (GHD), the first indication that fits in endocrine paradigm: to replace the missing hormone. In 1985 FDA approved recombinant human GH (hGH) as the treatment of pediatric patients who have growth failure due to inadequate secretion of endogenous GH. Availability of hGH in unlimited amounts enhanced the number of indications of GH use. Pediatric endocrinologist started to promote and to apply use of hGH for height in short, but otherwise healthy children, with hormonal normalcy. Reasonable criticism of such praxis arises in the light of recent safety alerts. The unbearable lightness of prescribing growth hormone to every apparently or really short child is reaching epidemic progress in Serbia. When authorities in this low income country (estimated as developing), approved hGH for use in SGA (small for gestational age) children, use and misuse of hGH exploded. Socially acceptable height, the term applied by some endocrinologists actually means that society does not accept short people. The pharmaceutical companies go even further offering, besides growth acceleration, better and brighter future for potential patients, in whom the self-confidence is measured by centimeters of height. However, benefits of such treatment on quality of life were never confirmed. Children with severe growth failure and documented GHD should be treated undoubtedly, but use of hGH for height, so called cosmetic endocrinology, needs critical appraisal. Children and their parents should be informed about height prediction and long-term consequences.

Renal disease in Cockayne syndrome

BackgroundCockayne Syndrome (CS) is a rare autosomal recessive multi-systemic disorder, characterized; by developmental delay, microcephaly, severe growth failure and sensorial impairment. Renal complications have been reported but remain underinvestigated. The objective of this study was to perform a review of renal disease in a cohort of CS patients. MethodsWe retrospectively collected relevant clinical, biochemical and genetic data from a cohort of 136 genetically confirmed CS patients. Blood pressure (BP), proteinuria, albuminemia, uric acid, creatinine clearance, renal ultrasounds and renal biopsy result were analysed. ResultsThirty-two patients had a renal investigation. We found that 69% of investigated patients had a renal disorder and/or an elevated BP. Fifteen out of 21 patients (71% of investigated patients) had an increased BP, 10 out of 16 patients (62% of investigated patients) presented with proteinuria and 4 of them had a nephrotic syndrome. Thirteen patients out of 29 (45%) had a decreased Glomerular Filtration Rate (GFR), 18 out of 25 patients (72%) had a hyperuricemia. No correlation with the genetic background or clinical types of CS was found, except for the renal clearance. ConclusionsRenal disease, increased blood pressure and hyperuricemia were highly prevalent in our study. We believe that CS patients should benefit from a nephrological follow-up and that anti-uric acid drug and Angiotensin-converting enzyme (ACE) inhibitor should be discussed in these patients.

Immunosuppressive Total Nodal Irradiation–Based Reconditioning Regimens After Graft Rejection or Graft Failure in Pediatric Patients Treated With Myeloablative Allogeneic Hematopoietic Cell Transplantation

This retrospective analysis aimed to address the efficacy of total nodal irradiation (TNI)-based reconditioning regimens in pediatric patients with graft failure/rejection after allogeneic hematopoietic cell transplantation. Thirty-three pediatric patients with malignant (n=25) and nonmalignant diseases (n=8) were treated with a TNI-based reconditioning regimen. All patients received a 7-Gy single dose combined with anti-T lymphocyte antibody OKT3 (n=16), anti-thymocyte globulin (n=24), fludarabine (n=31), and/or thiotepa (n=28), followed by an infusion of peripheral blood stem cells (n=31) or bone marrow transplant (n=2). Twenty-eight of 33 patients had haploidentical family donors. After a median of 11days, engraftment was seen in 32 of 33 children. Two children died 34days after retransplantation because of either disease relapse or treatment-related multiple organ failure. Severe acute toxicity was reported in only 1 child (systemic inflammatory response syndrome-like reaction; recovery after cortisone treatment). The average follow-up was 60.2months (range, 1.1-162.5months). Event-free and overall survival rates at 2/5years follow-up were 62.0%/58.6% and 65.1%/61.7%, respectively. Despite sustained engraftment, 12 patients died from disease relapse (n=3), Moschkowitz syndrome (n=1), or multiple organ failure (n=8). Follow-up data were available for 18 of 21 survivors, with a median follow-up of 92.8months (range, 3.6-162.5months). Hypothyroidism was present in 78.6% of patients, and sex/growth hormonal insufficiencies were reported for 37.5%. Mean forced expiratory volume in 1second after TNI was 84%; mean vital capacity was 79%. Severe growth failure (<3rd percentile) occurred in 28.6% (height) and 35.7% (weight) of patients. No secondary malignancies were reported. In the high-risk group of patients with graft failure/rejection after allogeneic hematopoietic cell transplantation, the TNI-based reconditioning regimen seems to allow sustained engraftment combined with a favorable toxicity profile, leading to long-term event-free and overall survival. Late toxicity after a median follow-up of over 7.5years includes growth failure, manageable hormonal deficiencies, and a low risk of decrease of lung function.

Dysregulatory syndromes: the role of signal transducers and activators of transcription.

A comparative description of dysregulatory syndromes with mutations in signal transducer and activator of transcription (STAT) genes. STAT 1, 3 and 5b loss of function (LOF) and gain of function (GOF) mutations are a heterogeneous group of genetic disorders that range from immunodeficiency (ID) to autoimmune disease (AID), depending on the underlying signalling pathway defect. Between them, there are clear overlapping and differences in clinical presentation and laboratory findings. Dysregulatory syndromes due to LOF and GOF mutations in STAT1, 3 and 5b are a particular group of primary immunodeficiencies (PIDs) in which AID may be the predominant finding in addition to infections susceptibility. STAT1 GOF mutations were described as the major cause of chronic mucocutaneous candidiasis, while activating STAT3 mutations result in early-onset multiorgan autoimmunity and ID. Human STAT5b deficiency is a rare disease that also involves ID and severe growth failure. In recent years, the identification of the genes involved in these disorders allowed to differentiate these overlapping syndromes in order to choose the most effective therapeutic options.

Gynecologic assessment of 19 adult females with cartilage-hair hypoplasia \u2013 high rate of HPV positivity

BackgroundPatients with cartilage-hair hypoplasia (CHH), a rare metaphyseal chondrodysplasia, manifest severe growth failure, variable immunodeficiency and increased risk of malignancies. The impact of CHH on gynecologic and reproductive health is unknown. Vulnerability to genital infections may predispose CHH patients to prolonged human papillomavirus (HPV) infections potentially leading to cervical, vaginal and vulvar cancer.MethodsWe carried out gynecologic evaluation, pelvic ultrasound and laboratory assessment in 19 women with genetically confirmed CHH. All patients were clinically examined and retrospective data were collected from hospital records.ResultsThe women ranged in age from 19.2 to 70.8 years (median 40.8 years) and in height from 103 to 150 cm (median 123 cm). All women had undergone normal pubertal development as assessed by breast development according to Tanner scale and by age of menarche (mean 12.5 yrs., range 11–14 yrs). Despite significant short stature and potentially small pelvic diameters, a well-developed uterus with fairly normal size and shape was found by pelvic ultrasound in most of the patients. Ovarian follicle reserve, assessed by ultrasound was normal in relation to age in all premenopausal women it could be assessed (12 cases). Anti-Müllerian hormone was normal in relation to age in 17 women (89%). HPV was detected in 44% (8/18) and three women carried more than one HPV serotype; findings did not associate with immunological parameters. Three patients had a concurrent cell atypia in Pap smear.ConclusionsPubertal development, reproductive hormones and ovarian structure and function were usually normal in women with CHH suggesting fairly normal reproductive health. However, the immunodeficiency characteristic to CHH may predispose the patients to HPV infections. High prevalence of HPV infections detected in this series highlights the importance of careful gynecologic follow up of these patients.

A second GH Receptor pseudoexon mutation causing frameshift and severe postnatal growth failure

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

A novel GHR pseudoexon mutation causing frameshift and severe postnatal growth failure

A novel GHR pseudoexon mutation causing frameshift and severe postnatal growth failure

Growth morbidity in extremely low birth weight survivors of necrotizing enterocolitis at discharge and two-year follow-up

PurposeThe purpose of this study was to examine postnatal growth outcomes and predictors of growth failure at 18–24months corrected age among extremely low birth weight (ELBW) survivors of necrotizing enterocolitis (NEC) compared to survivors without NEC. MethodsData were collected prospectively on ELBW (22–27weeks gestation or 401–1000g birth weight) infants born 2000–2013 at 46 centers participating in the Vermont Oxford Network follow-up project. Severe growth failure was defined as <3rd percentile weight-for-age. ResultsThere were 9171 evaluated infants without NEC, 416 with medical NEC, and 462 with surgical NEC. Rates of severe growth failure at discharge were higher among infants with medical NEC (56%) and surgical NEC (61%), compared to those without NEC (36%). At 18–24months follow-up, rates of severe growth failure decreased and were similar between without NEC (24%), medical NEC (24%), and surgical NEC (28%). On multivariable analysis, small for gestational age, chronic lung disease, severe intraventricular hemorrhage or cystic periventricular leukomalacia, severe growth failure at discharge, and postdischarge tube feeding predicted <3rd percentile weight-for-age at follow-up. ConclusionsELBW survivors of NEC have higher rates of severe growth failure at discharge. While NEC is not associated with severe growth failure at follow-up, one quarter of ELBW infants have severe growth failure at 18–24months. Type of studyPrognosis study. Level of evidenceII

A defect in the inner kinetochore protein CENPT causes a new syndrome of severe growth failure.

Primordial growth failure has been linked to defects in the biology of cell division and replication. The complex processes involved in microtubule spindle formation, organization and function have emerged as a dominant patho-mechanism in these conditions. The majority of reported disease genes encode for centrosome and centriole proteins, leaving kinetochore proteins by which the spindle apparatus interacts with the chromosomes largely unaccounted for. We report a novel disease gene encoding the constitutive inner kinetochore member CENPT, which is involved in kinetochore targeting and assembly, resulting in severe growth failure in two siblings of a consanguineous family. We herein present studies on the molecular and cellular mechanisms that explain how genetic mutations in this gene lead to primordial growth failure. In both, affected human cell lines and a zebrafish knock-down model of Cenpt, we observed aberrations in cell division with abnormal accumulation of micronuclei and of nuclei with increased DNA content arising from incomplete and/or irregular chromosomal segregation. Our studies underscore the critical importance of kinetochore function for overall body growth and provide new insight into the cellular mechanisms implicated in the spectrum of these severe growth disorders.

Can growth hormone treatment improve growth in children with severe growth failure due to anorexia nervosa? A preliminary pilot study.

Background/AimsGrowth failure is a difficult but key aspect of care in children with anorexia nervosa (AN). The effects of hGH therapy have not been studied. The aim was to investigate the effect of hGH treatment on height velocity (HV) in children with AN.MethodsWe carried out a retrospective observational study. Ten girls diagnosed with AN at 10.0 ± 1.9 years, with prolonged severe growth failure (HV < 2.5 cm/year for at least 18 months) at the age of 13.3 ± 1.1 years and delayed puberty after nutritional rehabilitation, were treated with hGH (0.040 mg/kg/day) from a bone age of 10.9 ± 1.7 years until they reached adult height. Height and HV were measured before treatment and at 12-month intervals during treatment.ResultsMean body mass index SDS remained unchanged, but HV increased significantly, from a median of 1.0 (0.7–2.1) to 7.1 (6.0–9.5) cm/year after one year (P < 0.002) and 5.6 (4.8–6.2) cm/year after two years of treatment. Height SDS increased from −2.2 ± 1.3 to −1.6 ± 1.3 after one year (P < 0.002) and −1.1 ± 1.5 after two years of GH treatment. Adult height (−0.1 ± 1.0 SDS) was close to target height after 3.6 ± 1.4 years of GH treatment. Serum IGF-I levels increased significantly during treatment (P < 0.01). The treatment was well tolerated.ConclusionsThis proof-of-concept study shows that hGH treatment is associated with significant improvements in linear growth in adolescents with AN and severe growth failure. A randomized placebo-controlled trial is required to determine the ultimate impact of GH treatment in patients with this severe, rare condition.

Severe growth deficiency, microcephaly, intellectual disability, and characteristic facial features are due to a homozygous QARS mutation.

Glutaminyl tRNA synthase is highly expressed in the developing fetal human brain. Mutations in the glutaminyl-tRNA synthetase (QARS) gene have been reported in patients with progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. We have previously reported a new recessive syndrome of severe linear growth retardation, poor weight gain, microcephaly, characteristic facial features, cutaneous syndactyly of the toes, high myopia, and intellectual disability in two sisters of Ashkenazi-Jewish origin (Eur J Med Genet 2014;57(6):288-92). Homozygosity mapping and whole exome sequencing revealed a homozygous missense (V476I) mutation in the QARS gene, located in the catalytic domain. The patient's fibroblasts demonstrated markedly reduced QARS amino acylation activity in vitro. Furthermore, the same homozygous mutation was found in an unrelated girl of Ashkenazi origin with the same phenotype. The clinical presentation of our patients differs from the original QARS-associated syndrome in the severe postnatal growth failure, absence of epilepsy, and minor MRI findings, thus further expanding the phenotypic spectrum of the glutaminyl-tRNA synthetase deficiency syndromes.

Association between neonatal morbidities and head growth from birth until discharge in very-low-birthweight infants born preterm: a population-based study.

To evaluate the possible association between major neonatal morbidities and poor head growth from birth to discharge home in very-low-birthweight (VLBW) infants born preterm. Population-based observational study comprising 12 992 infants (6340 male, 6652 female) of 24 to 32 weeks' gestation, and birthweight ≤1500g. Severe head growth failure (HGF) was defined as a decrease in head circumference z-score >2 z-scores, and moderate HGF as a decrease of 1 to 2 z-scores. Multinomial logistic regression analysis was applied to determine morbidities associated with HGF. Severe HGF occurred in 4.5% and moderate HGF in 20.9% of infants. Each unit increase in head circumference z-score at birth was associated with increased odds for severe and moderate HGF (odds ratios [OR] 5.29, 95% confidence intervals [CI] 4.67-6.00, and OR 2.38, 95% CI 2.23-2.54 respectively). Both severe and moderate HGF were associated with respiratory distress syndrome (OR 2.03, 95% CI 1.58-2.62, and OR 1.66, 95% CI 1.48-1.85 respectively); bronchopulmonary dysplasia (OR 3.38, 95% CI 2.33-4.91, and OR 1.87, 95% CI 1.52-2.30 respectively); necrotizing enterocolitis (OR 2.89, 95% CI 2.04-4.09, and OR 1.72, 95% CI 1.38-2.16 respectively), and sepsis (OR 2.06, 95% CI 1.69-2.50, and OR 1.38, 95% CI 1.24-1.53 respectively). Major neonatal morbidities were associated with HGF in VLBW infants born preterm. Identification of whether this is a direct effect of these morbidities or mediated through nutritional or growth factors may enable interventions to improve postnatal head growth of infants born preterm.